Download Botulism Infection Control

BOTULISM
Outline
AUGUST 2005
Agent
Epidemiology
Clinical Features
Differential Diagnosis
Laboratory Diagnosis
By law, health care providers must report
suspected or confirmed Botulism to the local
health department immediately (within 1 hr).
Even a single case of Botulism is considered an
outbreak and is a public health emergency.
Treatment and Prophylaxis
Infection Control
References
To report: call SFDPH communicable disease
control (24/7 Tel: 415-554-2830).
Upon receipt, SFDPH will initiate the public health
response and can facilitate lab testing.
AGENT
Botulism is an intoxication caused by botulinum toxin, which is produced by Clostridium botulinum
and, rarely, by other Clostridium species.
Organism.
Clostridium botulinum is a gram-positive, strictly anaerobic, spore-forming bacillus
commonly isolated from soil and from marine and lake sediments. There are several strains, all of
which elaborate toxin.
C. botulinum bacteria are not, in and of themselves, toxic to humans;
disease is caused by exposure to the bacterial toxin.
Toxin.
There are seven serotypes of the toxin, labeled A through G.
Types A, B, and E (and
rarely, F) cause natural disease in humans. Botulinum toxins are colorless, odorless and tasteless,
and are the most lethal toxins known, causing death at doses of <1 mcg.
The toxin is inactivated
by heating to 100°C for 1 minute, 85°C for 5 minutes, or 80°C for 20 minutes. Antibiotics have no
activity against the toxin itself.
Spores. In response to unfavorable environmental conditions (changes in pH, temperature, and
water or nutrient availability), C. botulinum bacteria “sporulate” – i.e. they become dormant, do
not reproduce, and alter their cellular processes to increase resistance to chemicals, heat, air, and
drying.
Thus, C. botulinum spores are hardy, resistant to dessication, heat, UV light, and alcohols,
and can survive boiling for up to 4 hours. (They are, however, readily killed by chlorine solutions.)
Once the spores encounter more favorable conditions, such as are found in contact with human
tissues, they will “germinate,” thereby producing growing cells that are capable of reproducing and
elaborating toxin.
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EPIDEMIOLOGY
Botulinum Toxin as a Biological Weapon
Several countries, including the the USA, the Soviet Union, Japan, and Iraq have conducted
research on use of botulinum toxin as a biological weapon and may have stockpiled weapons
containing it. Likely modes of dissemination for toxin used as a weapon include:
•
Deliberate contamination of food or beverages.
Food or beverage items that are
possible vehicles for botulinum toxin are those which are not heat-processed at 85°C
(185°F) for 5 minutes before consumption, and those which are appropriately heatprocessed but then become contaminated sometime after processing has occurred. Thus,
even at typical pasteurization temperatures (74°C/165°F for 30 seconds), some of the
toxin would remain intact.
•
Dispersion of aerosolized toxin. Animal studies and rare cases of laboratory accidents
have confirmed the pathogenicity of aerosolized toxin.
Experts have estimated that 1 gm
of aerosolized botulinum toxin could kill up to 1.5 million people, though technical factors
would make such dissemination difficult.
•
Contamination of a water supply.
This is possible but felt to be unlikely due to the
large amount of toxin needed to contaminate a water supply.
Also, toxin is rapidly
inactivated by standard drinking water treatment, and is naturally inactivated in fresh
water within 3 to 6 days.
The following features of a botulism outbreak would suggest deliberate toxin release:
•
An outbreak involving a large number of cases
•
An outbreak caused by an unusual toxin type (C, D, F, or G) or involving type E
toxin without an apparent aquatic source
•
Multiple simultaneous outbreaks with or without an apparent source
•
Cases lack a common food exposure, but were in geographic proximity during the
week before symptom onset (suggests aerosol release)
Naturally Occurring Botulism
Naturally occurring botulism is a rare disease with an annual incidence of approximately 100 cases
in the USA.
Food-borne botulism is caused by ingestion of food contaminated with preformed botulinum
toxin.
In order for food-borne botulism to occur, the food item must be contaminated with C.
botulinum spores, the spores must survive food preservation methods and then germinate and
produce toxin under anaerobic, low-acid, warm conditions. Finally the food must not be reheated
sufficiently to inactivate the heat-labile toxin before the food is consumed (>85°C for 5 minutes).
Toxin types A, B, and E account for most cases of foodborne botulism.
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Between 1990 and 2000, there were a median of 14 food-borne botulism events annually in the
USA, with a median of 1 case per event. From 1994-2003 there were 30 cumulative cases of foodborne botulism reported in California, none occurring in San Francisco.
Food-borne botulism
(especially type E) is a significant public health problem among Alaskan natives due to
consumption of fermented meat from aquatic mammals and fish.
Wound botulism is caused by infection of a contaminated wound with C botulinum organisms,
and subsequent absorption into the circulation of locally produced toxin. Most cases are related to
injection drug use. In 2004, wound botulism was reported among 8 injection drug users in San
Francisco, in association with use of black tar heroin.
Infant botulism is caused by ingestion of C botulinum spores. The spores colonize the GI tract,
germinate, and produce toxin which is absorbed into the circulation. The source of spores typically
is unknown, although ingestion of corn syrup or raw honey accounts for some cases. From 19942003 there were 283 cumulative cases of infant botulism reported in California, none occurring in
San Francisco. Intestinal botulism similar to that in infants has been reported very rarely in adults.
Inhalational botulism does not occur in nature, but has been produced experimentally in
laboratory animals.
Three human cases occurred in 1962 in lab technicians working with
aerosolized botulinum toxin.
Botulinum toxin is also used therapeutically.
Purified, highly diluted, injectable botulinum
toxin is used to treat a range of spastic or autonomic muscular disorders such as cervical dystonia
and strabismus (toxin type B). Toxin type A is used in extremely minute doses for the treatment
of facial wrinkles (Botox®).
Systemic effects of the toxin have been noted very rarely after medical
use or misuse of the product.
CLINICAL FEATURES
Botulism is caused by exposure to botulinum toxin. Exposure to toxin may occur through several
mechanisms:
•
Ingestion of preformed toxin (food-borne)
•
Inhalation of preformed toxin
•
Local production of toxin by C. botulinum organisms in the GI tract (infant; intestinal)
•
Local production of toxin by C. botulinum organisms in devitalized tissue (wound)
Regardless of the route of intoxication the same neurologic syndrome develops. Botulinum toxin
acts at the neuromuscular junction of skeletal muscle neurons and cholinergic autonomic synapses.
It binds irreversibly to presynaptic receptors to inhibit the release of acetylcholine. The effect lasts
weeks to months, until the synapses and axonal branches regenerate. Death from botulism results
acutely from airway obstruction or paralysis of respiratory muscles.
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Botulism is characterized by acute afebrile descending symmetric paralysis.
Disease generally
begins with cranial nerve dysfunction and then progresses to muscle weakness, with the proximal
muscle groups involved first.
Severity of disease is variable, ranging from mild cranial nerve dysfunction to complete flaccid
paralysis.
Both the severity of disease and the rapidity of onset correlate with the amount of toxin
absorbed into the circulation.
BOTULISM: CLINICAL FEATURES
Incubation Period
•
12-72 hours (range 2 hrs - 8 days)
•
Dependent on dose of toxin
Early Presentation – cranial nerve abnormalities
•
Dysarthria
•
Blurred and/or double vision
•
Dry mouth
•
Ptosis
•
Symptoms may be slow in onset or rapidly progressive (dose-dependent)
Later Presentation – descending paralysis
Signs & Symptoms
•
Dysphonia, dysphagia
•
Symmetrical, descending progressive muscular weakness
•
Dilated or fixed pupils
•
Decreased gag reflex
•
Respiratory failure
•
Autonomic nerve dysfunction; may include urinary retention, orthostasis
•
Normal mental status, though may appear lethargic and have difficulty with
communication
Laboratory Findings
•
Normal sensory nerve function
•
Afebrile unless there is complicating infection
•
Normal CSF glucose, protein, cell count
•
Normal CBC
•
Normal imaging of brain and spine (CT scan or MRI)
Characteristic EMG findings include:
•
Incremental response (facilitation) to repetitive stimulation at 50 Hz
•
Short duration of motor unit potentials
•
Normal sensory nerve function
•
Normal nerve conduction velocity
DIFFERENTIAL DIAGNOSIS
Botulism is frequently misdiagnosed. A high index of suspicion is necessary for early presumptive
diagnosis as there are no readily available rapid confirmatory tests. Diagnosis is primarily made on
the basis of clinical presentation and epidemiologic evidence of potential exposure.
However it
must be recognized that in the event of bioterrorist attack, the source of exposure may be unclear.
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Important questions to ask:
•
Recent history of eating home-canned vegetable, fruit, and fish products
•
Other known individuals with similar symptoms
•
Recent travel to Alaska or consumption of Alaskan seafood products
•
Recent history of IVDU, particularly with black tar heroin or cocaine
Key features that distinguish botulism are the constellation of:
•
Descending paralysis
•
Characteristic EMG findings
•
Cranial nerves prominently involved
•
Absence of paresthesias
•
Symmetric bilateral impairment
•
Afebrile illness
•
Normal CSF studies
•
Normal mental status
Guillain-Barre syndrome
•
Tick paralysis
(particularly Miller-Fisher variant)
•
Poliomyelitis
•
Myasthenia gravis
•
CNS infections, particularly of brainstem
•
Stroke
•
CNS tumor
•
Intoxication with CNS depressants
•
Psychiatric illness (i.e. conversion
•
Lambert-Eaton syndrome
•
Diabetic neuropathy
•
Inflammatory myopathy
•
Sudden infant death syndrome
•
Paralytic shellfish poisoning
•
Magnesium intoxication
Other conditions to consider:
•
paralysis)
LABORATORY DIAGNOSIS
Diagnosis is primarily made on the basis of
clinical presentation.
Laboratory confirmation
can be achieved in most cases by detection of
botulinum toxin in serum via mouse bioassay,
in which mice are injected with the patient
sample and observed for the development of
characteristic symptoms. Detection of toxin is
dependent on the total dose of toxin absorbed
If you are testing or considering testing for
Botulism, you should:
ƒ IMMEDIATELY notify SFDPH
Communicable Disease Control (24/7 Tel:
415-554-2830). SFDPH can authorize and
facilitate testing, and will initiate the public
health response as needed.
and the time from symptom onset to testing.
The mouse test is able to detect fractional nanogram amounts of toxin. The test requires 1-4 days
to complete and is performed only at reference laboratories. Test results may be negative if the
samples were collected late or the quantity of toxin is small; thus lack of detection of botulinum
toxin does not necessarily rule out the diagnosis of botulism. Tests other than the mouse bioassay
are currently investigational.
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For mouse bioassay, obtain at least 30 cc of serum. (If directed by public health personnel, obtain
20-50 cc of stool, enema fluid and/or gastric aspirate.) Serum specimens must be taken before
antitoxin treatment in order to demonstrate the presence of botulinum toxin. The lab should be
notified if the patient has received Tensilon or “stigmine” drugs prior to testing. Serum, stool, and
gastric specimens should be kept refrigerated, not frozen.
Potentially contaminated food samples may be collected (10-50 gm), sealed, and transported
under refrigeration. Environmental specimens with potential contamination may be collected (soil,
50-100 gm; water >100 cc) and transported at room temperature.
In case of suspected inhalational exposure, toxin may be present in nasal mucosa for up to 24
hours. However the utility of nasal sampling is unknown.
Routine laboratory tests on serum and CSF are generally within normal limits unless a secondary
process has occurred. Cultures of blood, stool, sputum, and urine are not helpful in confirming a
diagnosis of botulism. Viable organisms are generally present only in wound or infant botulism.
Patients do not generally develop an antibody response due to the sub-immunogenic amount of
toxin necessary to produce disease.
TREATMENT AND PROPHYLAXIS
These recommendations are current as of this document date. SFDPH will provide periodic
updates as needed and situational guidance in response to events (www.sfdph.org/cdcp).
Supportive
care,
including
mechanical
ventilation
and
parenteral
nutrition,
and
timely
administration of botulinum antitoxin are the mainstays of care for botulism. Ventilatory support
may be required for several weeks or more.
With modern intensive care methods, case-fatality
rates for botulism in the USA have dropped to <10%.
Note: aminoglycosides and clindamycin are contraindicated for treatment of secondary infections
since they may exacerbate the neuromuscular blockade.
Antitoxin Treatment
To obtain antitoxin, phone SFDPH Communicable Disease Control (24/7 Tel: 415-5542830).
If the clinical picture is compatible with botulism, antitoxin may be released
emergently.
Antitoxin is most effective when given within 24 hours after symptom onset. It cannot reverse any
existing paralysis.
However it binds to any toxin remaining in the circulation and can slow
progression of further disease and potentially decrease the duration of ventilatory support and
increase the likelihood of survival.
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Antitoxin is provided by the CDC but is available for release only via state and local health
departments.
Once antitoxin is requested, it generally can be delivered within 12 hours.
The
currently available formulation is botulinum antitoxin bivalent for types A and B (licensed by FDA).
Botulinum antitoxin type E is investigational.
A trivalent preparation (types A, B, E) has been
discontinued. The military is testing a heptavalent antitoxin (type A through G).
One 10-ml vial of each preparation of antitoxin is sufficient to neutralize circulating toxin from most
naturally occurring intoxications. A repeat dose is not usually necessary.
Since antitoxin is of equine origin, hypersensitivity reactions, including anaphylaxis, serum
sickness, and febrile reactions have occurred in up to 9% of patients receiving antitoxin.
Skin
testing for hypersensitivity should be performed in all patients before administering antitoxin. If
skin testing is positive, the patient can be desensitized over several hours before the full dose of
antitoxin is administered.
Diphenhydramine and epinephrine should be available during
administration.
No Prophylaxis of Exposed, Asymptomatic Persons
An exposed person is defined as a person who has been directly exposed to botulinum neurotoxin.
In the case of a bioterrorist event, the exposure would most likely occur by inhalation of toxin.
There is currently no available post exposure prophylaxis for asymptomatic exposed
persons. Such persons should be educated regarding the signs and symptoms of clinical botulism
and instructed to seek medical care immediately if symptoms occur. As there is no prophylactic
measure for botulism exposure other than observation and early treatment in the event of
symptoms, exposed persons and their families may experience anxiety and/or somatic symptoms
that may include neurologic symptoms. These patients should be carefully assessed. Antitoxin
supplies are limited, and therapy will be reserved for patients with compatible neurological findings.
Pre-exposure immunization with botulinum toxoid is restricted to certain laboratory and military
personnel. Supplies are extremely limited and would not be available for the public.
INFECTION CONTROL*
These recommendations are current as of this document date. SFDPH will provide periodic
updates as needed and situational guidance in response to events (www.sfdph.org/cdcp).
Person-to-person transmission does not occur. Standard Precautions are adequate for the care
of patients with botulism. Patients do not require isolation.
*
For description of Precautions, see chapter on Infection Control
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REFERENCES
Arnon SS et al, for the Working Group on Civilian Biodefense. Botulinum toxin as a biological
weapon: medical and public health management. JAMA 2001;285(8):1059-81.
CDC. Drug Service: General information. (www.cdc.gov/ncidod/srp/drugs/formulary.html#1a)
CIDRAP. Botulism: Current, comprehensive information on pathogenesis, microbiology,
epidemiology, diagnosis, treatment, and prophylaxis. June 16, 2005.
(www.cidrap.umn.edu/cidrap/content/bt)
Franz DR, et al. Clinical recognition and management of patients exposed to biological warfare
agents. JAMA 1997;278(5):399-411.
LA County DHS. Terrorism Agent Information and Treatment Guidelines for Clinicians and
Hospitals. June 2003. (www.labt.org/Zebra.asp)
Olson KR. Botulism. In: Poisoning and Drug Overdose, 4th ed. McGraw Hill, NY, 2004.
SFDPH. San Francisco Communicable Disease Report, 1986-2003. May, 2005.
(www.sfdph.org/cdcp)
Shapiro RL, et al. Botulism surveillance and emergency response: a public health strategy for a
global challenge. JAMA 1997;278(5):433-5.
Werner SB, Passaro K, McGee J, et al. Wound botulism in California, 1951-1998: recent epidemic in
heroin injectors. Clin Infect Dis 2000;31:1018-24.
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